Abstract

In normal tissues, the expression of folate receptors is low and limited to cells that are important for embryonic development or for folate reabsorption. However, in several pathological conditions some cells, such as cancer cells and activated macrophages, overexpress folate receptors (FRs). This overexpression makes them a potential therapeutic target in the treatment of cancer and inflammatory diseases to obtain a selective delivery of drugs at altered cells level, and thus to improve the therapeutic efficacy and decrease the systemic toxicity of the pharmacological treatments. Two strategies have been used to achieve this folate receptor targeting: (i) the use of ligands with high affinity to FRs (e.g., folic acid or anti-FRs monoclonal antibodies) linked to the therapeutic agents or (ii) the use of nanocarriers whose surface is decorated with these ligands and in which the drug is encapsulated. This manuscript analyzes the use of FRs as a target to develop new therapeutic tools in the treatment of cancer and inflammatory diseases with an emphasis on the nanoformulations that have been developed for both therapeutic and imaging purposes.

Highlights

  • In recent decades, the use of targeted therapies that act selectively on target cells has increased considerably [1,2]

  • An antibody-functionalized nanoprobe that targets FRα has been prepared for Raman imaging. This nanosystem, which consists of gold nanostars covered with a silica shell that was functionalized with anti-FRα-monoclonal antibodies, demonstrated to be useful as an imaging tool in ovarian cancer models developed in mice

  • A progression free survival of 6.7 months [72]. Administered at these doses, mirvetuximab soravtansine conjugate showed a higher efficacy in platinum-resistant ovarian cancer patients compared with conventional chemotherapy with an objective response rate of 24 vs. 10% and a progression free survival of 4.8 vs. 3.3 months, being well tolerated

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Summary

Introduction

The use of targeted therapies that act selectively on target cells has increased considerably [1,2]. RFC-1 is a ubiquitously expressed antiporter in the intestine, hepatocytes, choroid plexus, and renal epithelial cells that uses the gradient of organic phosphate across the cell membrane to allow folate uptake at neutral pH and to show a low folate-binding affinity (Km = 1–10 μM) [14,15]. The intestine, hepatocytes, choroid plexus, and uptake renal epithelial cells of organic phosphate across the cell membrane to allow folate at neutral pHthat anduses the FRγ is primarily a secretory protein [18]. FR expression is largely limited of organic phosphate across the cell membrane tocontrast, allow folate uptake at neutral to show a low folate-binding affinity 3).inThe binding of FRglycoproteins ligands is as followed by macrophages the folate invaginatheir expression is low

Structure
Folic Acid-Cytotoxic Drug Conjugates
Folic Acid-Functionalized Nanoparticles
Anti-FR-Monoclonal Antibody-Drug Conjugates
Anti-FR-Monoclonal Antibody-Functionalized Nanoparticles
Anti-FRβ Monoclonal Antibody-Coated Nanoformulations
FR-Targeted-Nanoformulations in Inflammatory Bowel Disorders
FR-Targeted Nanoparticles to Cross the Blood–Brain Barrier
FR-Targeted Formulations as Imaging Strategy
Cancer Disease
Inflammatory Diseases
47 Sc-labeled folate conjugates containing an albumin binder
55 Co-labeled folate conjugates containing an albumin binder
Etarfolide
Vintafolide
Mirvetuximab Soravtansine
EC17 Conjugate
BMS-753493 Conjugate
EC1456 Conjugate
Current and Future Perspectives
Findings
Conclusions
Full Text
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